The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.
Here, we investigate the mechanism and function of LKB1, a Ser/Thr kinase mutated in Peutz-Jegher syndrome (PJS). We demonstrate that LKB1 physically associates with p53 and regulates specific p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in Peutz-Jegher patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. We propose that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.


Two novel Drosophila TAF(II)s have homology with human TAF(II)30 and are differentially regulated during development.
TFIID is a multiprotein complex composed of the TATA binding protein (TBP) and TBP-associated factors (TAF(II)s). The binding of TFIID to the promoter is the first step of RNA polymerase II preinitiation complex assembly on protein-coding genes. Yeast (y) and human (h) TFIID complexes contain 10 to 13 TAF(II)s. Biochemical studies suggested that the Drosophila (d) TFIID complexes contain only eight TAF(II)s, leaving a number of yeast and human TAF(II)s (e.g., hTAF(II)55, hTAF(II)30, and hTAF(II)18) without known Drosophila homologues. We demonstrate that Drosophila has not one but two hTAF(II)30 homologues, dTAF(II)16 and dTAF(II)24, which are encoded by two adjacent genes. These two genes are localized in a head-to-head orientation, and their 5' extremities overlap. We show that these novel dTAF(II)s are expressed and that they are both associated with TBP and other bona fide dTAF(II)s in dTFIID complexes. dTAF(II)24, but not dTAF(II)16, was also found to be associated with the histone acetyltransferase (HAT) dGCN5. Thus, dTAF(II)16 and dTAF(II)24 are functional homologues of hTAF(II)30, and this is the first demonstration that a TAF(II)-GCN5-HAT complex exists in Drosophila. The two dTAF(II)s are differentially expressed during embryogenesis and can be detected in both nuclei and cytoplasm of the cells. These results together indicate that dTAF(II)16 and dTAF(II)24 may have similar but not identical functions.


Disentangling true shape differences and experimenter bias: are dextral and sinistral snail shells exact mirror images?
IN THEORY, SNAILS CAN COME IN TWO ENANTIOMORPHS: either dextral (coiling clockwise) or sinistral (coiling counter-clockwise). In snail species where both forms are actually present, coiling direction is determined by a single gene with delayed maternal inheritance; there is no predictable relationship between a snail's own coiling genotype and its actual coiling direction. Because of this genetic decoupling, it might be expected that dextral and sinistral individuals would be exact mirror images of one another. However, indications exist that there is a subtle but detectable shape difference between dextral and sinistral individuals that derive from the same gene pool. In this paper, we attempt to detect such differences in 50 dextral and 50 sinistral individuals of Amphidromus inversus, a species of land snail that is consistently chirally dimorphic. Four out of 18 volunteers who measured the shells with Vernier calipers found that sinistrals are stouter to a significant degree. A similar result was found by one out of five volunteers who measured the shells from photographs. These results do not allow distinguishing between real shape differences and a handling bias of sinistral as compared with dextral shells. However, when the same set of shells was subjected to a geometric morphometric analysis, we were able to show that sinistrals indeed exhibit a slight but significant widening and twisting of the shell near the palatal and parietal apertural areas. This result is surprising because species of the subgenus Amphidromus s. str. share a long history of chiral dimorphism, and the species would be expected to have been purged from disadvantageous interactions between direction of coil and general shell shape. We conclude that selection on the shape differences is either very weak or constrained by the fact that the pleiotropic effects of the chirality gene are of importance very early in development only.


Analysis of tyrosine phosphorylation and phosphotyrosine-binding proteins in germinating seeds from Scots pine.
Protein tyrosine phosphorylation in angiosperms has been implicated in various physiological processes, including seed development and germination. In conifers, the role of tyrosine phosphorylation and the mechanisms of its regulation are yet to be investigated. In this study, we examined the profile of protein tyrosine phosphorylation in Scots pine seeds at different stages of germination. We detected extensive protein tyrosine phosphorylation in extracts from Scots pine (Pinus sylvestris L.) dormant seeds. In addition, the pattern of tyrosine phosphorylation was found to change significantly during seed germination, especially at earlier stages of post-imbibition which coincides with the initiation of cell division, and during the period of intensive elongation of hypocotyls. To better understand the molecular mechanisms of phosphotyrosine signaling, we employed affinity purification and mass spectrometry for the identification of pTyr-binding proteins from the extracts of Scots pine seedlings. Using this approach, we purified two proteins of 10 and 43 kDa, which interacted specifically with pTyr-Sepharose and were identified by mass spectrometry as P. sylvestris defensin 1 (PsDef1) and aldose 1-epimerase (EC:184.108.40.206), respectively. Additionally, we demonstrated that both endogenous and recombinant PsDef1 specifically interact with pTyr-Sepharose, but not Tyr-beads. As the affinity purification approach did not reveal the presence of proteins with known pTyr binding domains (SH2, PTB and C2), we suggest that plants may have evolved a different mode of pTyr recognition, which yet remains to be uncovered.


Protease-Mediated Growth of Staphylococcus aureus on Host Proteins Is opp3 Dependent.
Staphylococcus aureus has the ability to cause infections in multiple organ systems, suggesting an ability to rapidly adapt to changing carbon and nitrogen sources. Although there is little information about the nutrients available at specific sites of infection, a mature skin abscess has been characterized as glucose depleted, indicating that peptides and free amino acids are an important source of nutrients for the bacteria. Our studies have found that mutations in enzymes necessary for growth on amino acids, including pyruvate carboxykinase (ΔpckA) and glutamate dehydrogenase (ΔgudB), reduced the ability of the bacteria to proliferate within a skin abscess, suggesting that peptides and free amino acids are important for S. aureus growth. Furthermore, we found that collagen, an abundant host protein that is present throughout a skin abscess, serves as a reservoir of peptides. To liberate peptides from the collagen, we identified that the host protease, MMP-9, as well as the staphylococcal proteases aureolysin and staphopain B function to cleave collagen into peptide fragments that can support S. aureus growth under nutrient-limited conditions. Moreover, the oligopeptide transporter Opp3 is the primary staphylococcal transporter responsible for peptide acquisition. Lastly, we observed that the presence of peptides (3-mer to 7-mer) induces the expression of aureolysin, suggesting that S. aureus has the ability to detect peptides in the environment.IMPORTANCEStaphylococcus aureus has the ability to cause infections in a variety of niches, suggesting a robust metabolic capacity facilitating proliferation under various nutrient conditions. The mature skin abscess is glucose depleted, indicating that peptides and free amino acids are important sources of nutrients for S. aureus Our studies have found that mutations in both pyruvate carboxykinase and glutamate dehydrogenase, enzymes that function in essential gluconeogenesis reactions when amino acids serve as the major carbon source, reduce bacterial burden in a murine skin abscess model. Moreover, peptides liberated from collagen by host protease MMP-9 as well as the staphylococcal protease aureolysin support S. aureus growth in an Opp3-dependent manner under nutrient-limited conditions. Additionally, the presence of peptides induces aureolysin expression. Overall, these studies define one pathway by which S. aureus senses a nutrient-limiting environment and induces factors that function to acquire and utilize carbon from host-derived sources.


Understanding global infrared opacity and hot bands of greenhouse molecules with low vibrational modes from first-principles calculations: the case of CF4.
Fluorine containing molecules have a particularly long atmospheric lifetime and their very big estimated global warming potentials are expected to rapidly increase in the future. This work is focused on the global theoretical prediction of infrared spectra of the tetrafluoromethane molecule that is considered as a potentially powerful greenhouse gas having the largest estimated lifetime of over 50 000 years in the atmosphere. The presence of relatively low vibrational frequencies makes the Boltzmann population of the excited levels important. Consequently, the "hot bands" corresponding to transitions among excited rovibrational states contribute significantly to the CF4 opacity in the infrared even at room temperature conditions but the existing laboratory data analyses are not sufficiently complete. In this work, we construct the first accurate and complete ab initio based line lists for CF4 in the range 0-4000 cm-1, containing rovibrational bands that are the most active in absorption. An efficient basis set compression method was applied to predict more than 700 new bands and subbands via variational nuclear motion calculations. We show that already at room temperature a quasi-continuum of overlapping weak lines appears in the CF4 infrared spectra due to the increasing density of bands and transitions. In order to converge the infrared opacity at room temperature, it was necessary to include a high rotational quantum number up to J = 80 resulting in 2 billion rovibrational transitions. In order to make the cross-section simulation faster, we have partitioned our data into two parts: (a) strong & medium line lists with lower energy levels for calculation of selective absorption features that can be used at various temperatures and (b) compressed "super-line" libraries of very weak transitions contributing to the quasi-continuum modelling. Comparisons with raw previously unassigned experimental spectra showed a very good accuracy for integrated absorbance in the entire range of the reported spectra predictions. The data obtained in this work will be made available through the TheoReTS information system (http://theorets.univ-reims.fr, http://theorets.tsu.ru) that contains ab initio born line lists and provides a user-friendly graphical interface for a fast simulation of the CF4 absorption cross-sections and radiance under various temperature conditions from 80 K to 400 K.


Translational thermotolerance in Saccharomyces cerevisiae.
While protein synthesis is rapidly inactivated in Saccharomyces cerevisiae, cells shifted from log growth at 30 degrees C to 43 degrees C, a 1-h 37 degrees C treatment given to cells just prior to the shift to 43 degrees C partially blocks this inactivation. By contrast, such a pre-heat shock treatment has no protective effect on translational inactivation at 45 degrees C or higher. Cells allowed to approach stationary phase not only develop an enhanced thermotolerance relative to log cells but also exhibit a pronounced resistance to inactivation of protein synthesis at 43 degrees C as well as at 45 degrees C. We have found that this 'translational thermotolerance' can also be induced in S. cerevisiae by briefly treating log phase cells at 30 degrees C with cycloheximide. Using such a procedure to induce stabilization of protein synthesis at 43 degrees C, we have been able to show that heat shock-induced proteins are not responsible for the establishment of this protective effect. This work shows that enhanced thermotolerance can be induced in log cells even after a shift to 43 degrees C, as long as a prior translational thermotolerance has been established. Furthermore, we show that the capacity of plateau cells to maintain translation at 43 degrees C contributes significantly to their state of enhanced thermotolerance.


Lipid surface modifications increase mesoporous silica nanoparticle labeling properties in mesenchymal stem cells.
Nanoparticles have emerged as promising cell-labeling tools, as they can be precisely tailored in terms of chemical and physical properties. Mesoporous silica nanoparticles (MSNs), in particular, are easily tunable with regard to surface and core chemistry, and are able to confine dyes and drug molecules efficiently. The aim of this study was to investigate the effect of lipid and polyethylene glycol (PEG) surface modifications on MSN stem-cell-tracking abilities. Lipid and PEG surface functionalized MSNs were synthesized and the effect of surface functionalization on cell internalization, proliferation, differentiation and cell proteomics was investigated in patient derived mesenchymal stem cells (MSCs). MSNs and lipid surface-modified MSNs were internalized by >80% of the MSC population, with the exception of nanoparticles modified with short PEG chains (molecular weight 750 [MSN-PEG750]). Lipid-modified MSNs had higher labeling efficiency with maximum uptake after 2 hours of exposure and were in addition internalized 17 times higher compared to unmodified MSNs, without negatively affecting differentiation capacity. Using a mass-spectrometry-based label-free quantitative proteomics approach, we show that MSN labeling leads to the up- and downregulation of proteins that were unique for the different surface-modified MSNs. In addition, functional enrichments were found in human MSCs labeled with MSNs, MSN-PEG750, and lipid-modified MSNs. Here we show that organic modifications with lipids and PEGylation can be used as a promising strategy to improve MSN labeling capabilities. In particular, we show that lipid modifications can optimize such probes in three distinct ways: significantly improved signal strength, a barrier for sustained release of additional probes, and improved stem-cell-labeling efficiency.


Automatic Updates of Transition Potential Matrices in Dempster-Shafer Networks Based on Evidence Inputs.
Sensor fusion is a topic central to aerospace engineering and is particularly applicable to unmanned aerial systems (UAS). Evidential Reasoning, also known as Dempster-Shafer theory, is used heavily in sensor fusion for detection classification. High computing requirements typically limit use on small UAS platforms. Valuation networks, the general name given to evidential reasoning networks by Shenoy, provides a means to reduce computing requirements through knowledge structure. However, these networks use conditional probabilities or transition potential matrices to describe the relationships between nodes, which typically require expert information to define and update. This paper proposes and tests a novel method to learn these transition potential matrices based on evidence injected at nodes. Novel refinements to the method are also introduced, demonstrating improvements in capturing the relationships between the node belief distributions. Finally, novel rules are introduced and tested for evidence weighting at nodes during simultaneous evidence injections, correctly balancing the injected evidenced used to learn the transition potential matrices. Together, these methods enable updating a Dempster-Shafer network with significantly less user input, thereby making these networks more useful for scenarios in which sufficient information concerning relationships between nodes is not known a priori.


Perceptual image hashing based on virtual watermark detection.
This paper proposes a new robust and secure perceptual image hashing technique based on virtual watermark detection. The idea is justified by the fact that the watermark detector responds similarly to perceptually close images using a non embedded watermark. The hash values are extracted in binary form with a perfect control over the probability distribution of the hash bits. Moreover, a key is used to generate pseudo-random noise whose real values contribute to the randomness of the feature vector with a significantly increased uncertainty of the adversary, measured by mutual information, in comparison with linear correlation. Experimentally, the proposed technique has been shown to outperform related state-of-the art techniques recently proposed in the literature in terms of robustness with respect to image processing manipulations and geometric attacks.


Effect of surface modification of Ti-6Al-4V alloy by electron cyclotron resonance plasma oxidation.
Ti-6Al-4V alloy is used as biomaterials for dental and orthopedic implants because of their excellent biocompatibilities and mechanical properties. However, it is unclear that electron cyclotron resonance (ECR) plasma oxidation can create the oxide films on Ti-6Al-4V alloy surface, and this technique improves the ability of its osseointegration. The purpose of this study was to investigate the characteristics and calcification ability of the oxide films. X-ray diffraction (XRD) peaks of rutile phase were intensified with increasing the temperature. Scanning electron microscopy (SEM) images showed a crater-like structure, and bonding strengths between the substrate and oxide film reached a maximum at 400°C. Calcium phosphate (CaP) compounds after calcification process were identified as octacalcium phosphate (OCP) and precipitation amount was maximized at 400°C. The results suggested that the altered surface of Ti-6Al-4V alloy by ECR plasma oxidation might have the potential of accelerating the ability of its osseointegration through enhancement of OCP.


A systems analysis and conceptual system dynamics model of the livestock-derived food system in South Africa: A tool for policy guidance.
Global food production systems are currently under scrutiny, in particular the health, nutrition, and environmental impacts of livestock-derived food (LDF). Despite South Africa's recent socio-economic transformation and increased per-capita LDF consumption, the triple burden of malnutrition persists. Policy responses to such complex problems often fail because of linear thinking with short-term goals. However, a systems approach helps identify root causes, feedback mechanisms, potential unintended consequences, and opportunities for integrated, durable solutions. Participation in the systems-thinking process improves stakeholder understanding and buy-in. Our participatory workshop facilitated the development of a systems map for South African LDF, identifying key system elements, linkages, and nexus points. The latter included climate change, land access and management, livestock management and productivity, farming systems, food safety, policy articulation, agricultural knowledge, and income. Based on these findings, and an overview of related literature, we produced a conceptual system dynamics model of the LDF system. We identified key vari-ables and causal relationships, vicious and virtuous loops, system archetypes, conceptual stock and flows, and links to Sustainable Development Goals. The LDF system is complex and dynamic, with a dominance of commercial enterprises across agriculture and food retail, presenting barriers for small and medium-scale individuals. Other key elements relate to population growth and urbanization, land access, deregulation of international trade, climate change vulnerability, feed production limitations, and food safety. Our work provides a unique reference for policymakers, identifying the need for deep structural change, highlighting the possible unintended consequences, and thereby mitigating the risk of system destabilization.


Spinal cord injury in the United States Army Special Forces.
Spinal cord injury (SCI) is an area of key interest in military medicine but has not been studied among the US Army Special Forces (SF), the most elite group of US soldiers. SF soldiers make up a disproportionate 60% of all Special Operations casualties. The objective of this study was to better understand SCI incidence in the SF, its mechanisms of acquisition, and potential areas for intervention by addressing key issues pertaining to protective equipment and body armor use. An electronic survey questionnaire was formulated with the close collaboration of US board-certified neurosurgeons from the Mount Sinai Hospital and Cleveland Clinic Departments of Neurosurgery, retired military personnel of the SF, and operational staff of the Green Beret Foundation. The survey was sent to approximately 6000 SF soldiers to understand SCI diagnosis and its associations with various health and military variables. The response rate was 8.2%. Among the 492 respondents, 94 (19.1%) self-reported an SCI diagnosis. An airborne operation was the most commonly attributed cause (54.8%). Moreover, 87.1% of SF soldiers reported wearing headgear at the time of injury, but only 36.6% reported wearing body armor, even though body armor use has significantly increased in post-9/11 SF soldiers compared with that in their pre-9/11 counterparts. SCI was significantly associated with traumatic brain injury, arthritis, low sperm count, low testosterone, erectile dysfunction, tinnitus, hyperacusis, sleep apnea, posttraumatic stress disorder, major depressive disorder, and generalized anxiety disorder. Only 16.5% of SF soldiers diagnosed with SCI had been rescued via medical evacuation (medevac) for treatment. A high number of SF soldiers self-reported an SCI diagnosis. Airborne operations landings were the leading cause of SCI, which coincided with warfare tactics employed during the Persian Gulf War, Operation Iraqi Freedom, and other conflicts. A majority of SCIs occurred while wearing headgear and no body armor, suggesting the need for improvements in protective equipment use and design. The low rate of medevac rescue for these injuries may suggest that medical rescue was not attainable at the time or that certain SCIs were deemed minor at the time of injury.


Ethical issues at the end of life.
Providing good care for dying patients requires that physicians be knowledgeable of ethical issues pertinent to end-of-life care. Effective advance care planning can assure patient autonomy at the end of life even when the patient has lost decision-making capacity. Medical futility is difficult to identify in the clinical setting but may be described as an intervention that will not allow the intended goal of therapy to be achieved. Medical interventions, including artificial nutrition and hydration, can be withheld or withdrawn if this measure is consistent with the dying patient's wishes. Physicians caring for terminally ill patients receive requests for physician-assisted suicide. The physician should establish the basis for the request and work with the healthcare team to provide support and comfort for the patient. Physician-assisted suicide could negate the traditional patient-physician relationship and place vulnerable populations at risk. Physicians need to incorporate spiritual issues into the management of patients at the end of life. The integrity of the physician as a moral agent in the clinical setting needs to be recognized and honored. The physician has a moral imperative to assure good care for dying patients.


Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem.
Sweet perception promotes food intake, whereas that of bitterness is inhibitory. Surprisingly, the expression of sweet G protein-coupled taste receptor (GPCTR) subunits (T1R2 and T1R3) and bitter GPCTRs (T2R116, T2R118, T2R138 and T2R104), as well as the α-subunits of the associated signalling complex (αGustducin, Gα14 and αTransducin), in oral and extra-oral tissues from lean and obese mice, remains poorly characterized. We focused on the impact of obesity on taste receptor expression in brain areas involved in energy homeostasis, namely the hypothalamus and brainstem. We demonstrate that many of the GPCTRs and α-subunits are co-expressed in these tissues and that obesity decreases expression of T1R3, T2R116, Gα14, αTrans and TRPM5. In vitro high levels of glucose caused a prominent down-regulation of T1R2 and Gα14 expression in cultured hypothalamic neuronal cells, leptin caused a transient down-regulation of T1R2 and T1R3 expression. Intriguingly, expression differences were also observed in other extra-oral tissues of lean and obese mice, most strikingly in the duodenum where obesity reduced the expression of most bitter and sweet receptors. In conclusion, obesity influences components of sweet and bitter taste sensing in the duodenum as well as regions of the mouse brain involved in energy homeostasis, including hypothalamus and brainstem.


Ammonia promotes accumulation of intracellular cAMP in differentiating amoebae of Dictyostelium discoideum.
We used sporogenous mutants of Dictyostelium discoideum to investigate the mechanism(s) by which exogenous NH4Cl and high ambient pH promote spore formation during in vitro differentiation. The level of NH4Cl required to optimize spore formation is correlated inversely with pH, indicating that NH3 rather than NH4+ is the active species. The spore-promoting activity of high ambient pH (without exogenous NH4Cl) was eliminated by the addition of an NH3-scavenging cocktail, suggesting that high pH promotes spore differentiation by increasing the ratio of NH3:NH4+ secreted into the medium by developing cells. High ammonia levels and high pH stimulated precocious accumulation of intracellular cAMP in both sporogenous and wild-type cells. In both treatments, peak cAMP levels equaled or exceeded control levels and were maintained for longer periods than in control cells. In contrast, ammonia strongly inhibited accumulation of extracellular cAMP without increasing the rate of extracellular cAMP hydrolysis, indicating that ammonia promotes accumulation of intracellular cAMP by inhibiting cAMP secretion. These results are consistent with previous observations that factors that raise intracellular cAMP levels increase spore formation. Lowering intracellular cAMP levels with caffeine or progesterone inhibited spore formation, but simultaneous exposure to these drugs and optimal concentrations of NH4Cl restored both cAMP accumulation and spore formation to normal levels. These data suggest that ammonia, which is a natural Dictyostelium morphogen, favors spore formation by promoting accumulation or maintenance of high intracellular cAMP levels.


Dual roles of F123 in protein homodimerization and inhibitor binding to biotin protein ligase from Staphylococcus aureus.
Protein biotinylation is catalysed by biotin protein ligase (BPL). The most characterized BPL is from Escherichia coli where it functions as both a biotin ligase and a homodimeric transcriptional repressor. Here we investigated another bifunctional BPL from the clinically important Staphylococcus aureus (SaBPL). Unliganded SaBPL (apo) exists in a dimer-monomer equilibrium at low micromolar concentrations - a stark contrast to E. coli BPL (EcBPL) that is monomeric under the same conditions. EMSA and SAXS analysis demonstrated that dimeric apo SaBPL adopted a conformation that was competent to bind DNA and necessary for it to function as a transcription factor. The SaBPL dimer-monomer dissociation constant was 5.8-fold tighter when binding the inhibitor biotin acetylene, but unchanged with biotin. F123, located in the dimer interface, was critical for homodimerization. Inhibition studies together with surface plasmon resonance analyses revealed a strong correlation between inhibitor potency and slow dissociation kinetics. A 24-fold difference in Ki values for these two enzymes was explained by differences in enzyme:inhibitor dissociation rates. Substitution of F123 in SaBPL and its equivalent in EcBPL altered both inhibitor potency and dissociation. Hence, F123 in SaBPL has novel roles in both protein dimerization and ligand-binding that have not been reported in EcBPL.


Clinical Features and Pathophysiology of Disorders of Arousal in Adults: A Window Into the Sleeping Brain.
Introduction: Disorders of Arousal (DoA) are NREM parasomnias that have been typically regarded as self-limited childhood manifestations. It is now clear that DoA can persist in adults, often presenting with distinctive characteristics. So far, few studies have described the clinical course and characteristics of DoA in adulthood, therefore a large part of their semiology is ignored. The aim of this study is to describe the clinical manifestations of DoA in an adult population and to provide a pathophysiological interpretation of their features. Methods: We screened our database for all 1,600 adult (≥15 years) patients with sleep-related motor behaviors between 1995 and 2016. We identified 45 patients with typical DoA episodes, of whom a complete history, neurological examination and diagnostic video-polysomnography (VPSG) were available. All patients provided a detailed description of their episodes (with particular regards to semiology, frequency, and association with stressful life events) in different life periods. VPSG recordings were reviewed and DoA episodes were identified and assigned to three different categories according to their complexity. Results: Our population was composed of 45 adult patients ranging between 15 and 76 years. Sleepwalking was reported by 86% of patients, possibly associated with complex interactions with the environment and violent behaviors in 53% of cases; distressing mental contents were reported by 64%. Recall of the episodes was reported in 77% of patients. Non-restorative sleep was reported in 46% of patients. Stress was a potential episode trigger in 80% of patients. VPSG recordings documented 334 DoA episodes. According to our classification of motor patterns, 282 episodes (84%) were Simple Arousal Movements (SAMs), 34 (10%) Rapid Arousal Movements (RAMs) and 18 (5%) Complex Arousal Movements (CAMs). Discussion: Our study confirms that DoA in adulthood present with distinctive characteristics, such as non-restorative sleep, violence and complex, or bizarre behaviors. Alternative classifications of DoA based on motor patterns could be useful to characterize DoA episodes in adults, as different motor patterns often coexist in the same individual and minor episodes are more common but generally underreported by patients. Prospective studies are needed for a definitive characterization of DoA in adulthood throughout the life course.


Cucurbit[n]uril-based coordination chemistry: from simple coordination complexes to novel poly-dimensional coordination polymers.
Cucurbit[n]urils are a family of molecular container hosts bearing a rigid hydrophobic cavity and two identical carbonyl fringed portals. They have attracted much attention in supramolecular chemistry because of their superior molecular recognition properties in aqueous media. This review highlights the recent advances and challenges in the field of cucurbit[n]uril-based coordination chemistry. It not only presents progress in the knowledge of such macrocyclic compounds, which range from simple to complicated architectures, but also presents new routes of synthesis and their advantages in hybrid porous solids. The concept of structure "inducer" for their structural design to achieve predictable structures and controlled pores is described. The large pore sizes and hydrophobic cavities of these compounds that lead to unprecedented properties and potential applications are also discussed.


[Emergence of beta-lactam-dependent Bacillus cereus associated with prolonged treatment with cefepime in a neutropenic patient].
Antibiotic dependence in clinical isolates has been reported, albeit rarely, such as vancomycin-dependent enterococcus and beta-lactam-dependent Staphylococcus saprophyticus. We report herein a clinical isolate of beta-lactam-dependent Bacillus cereus. A 16-yr-old female was admitted on 8 September 2005 with neutropenic fever during chemotherapy following surgical removal of peripheral neuroectodermal tumor. She had had an indwelling chemoport since August 2004 and experienced B. cereus bacteremia three times during the recent 3-month period prior to the admission; the bacteremias were treated with cefepime-based chemotherapy. On hospital days 1 and 3, B. cereus was isolated from blood drawn through the chemoport. The isolates were resistant to penicillin, ceftriaxone, and erythromycin, and susceptible to vancomycin and ciprofloxacin. The isolate of hospital day 3 grew only nearby the beta-lactam disks including penicillin and ceftriaxone on disk diffusion testing. The beta-lactam-dependent isolate required a minimum of 0.064 microg/mL of penicillin or 0.023 microgram/mL of cefotaxime for growth, which was demonstrated by E test (AB Biodisk, Sweden). Light microscopy and transmission electron microscopy revealed a marked elongation of the dependent strain compared with the non-dependent strain. Prolonged therapy with beta-lactams in the patient with an indwelling intravenous catheter seemed to be a risk factor for the emergence of beta-lactam-dependence in B. cereus.


'Nesting networks': Women's experiences of social network support in high-risk pregnancy.
Social support, an individual's social relationships (both online and offline), may provide protection against adverse mental health outcomes, such as anxiety and depression, which are high in women who have been hospitalised with high-risk pregnancy. This study explored the social support available to women at higher risk of preeclampsia during pregnancy by examining personal social networks. Semi-structured interviews were accompanied by social network mapping using the web-based social networking tool GENIE. England. Twenty-one women were recruited, of whom 18 were interviewed both during pregnancy and postnatally between April 2019 and April 2020. Nineteen women completed maps pre-natally, 17 women completed maps pre-natally and post-natally. Women were taking part in the BUMP study, a randomised clinical trial that included 2441 pregnant individuals at higher risk of preeclampsia and recruited at a mean of 20 weeks' gestation from 15 hospital maternity units in England between November 2018 and October 2019. Women's social networks tightened during pregnancy. The inner network changed most dramatically postnatally with women reporting fewer network members. Interviews revealed networks were primarily 'real-life' rather than online social networks, with members providing emotional, informational, and practical support. Women with a high-risk pregnancy valued the relationships they developed with health professionals during pregnancy, and would like their midwife to have a more central role in their networks by providing informational and, where needed, emotional support. The social network mapping data supported the qualitative accounts of changing networks across high-risk pregnancy. Women with a high-risk pregnancy seek to build "nesting networks" to support them through pregnancy into motherhood. Different types of support are sought from trusted sources. Midwives can play a key role. As well as highlighting other potential needs during pregnancy and the ways in which they can be met, support from midwives has a key role. Through talking to women early in their pregnancy, signposting information and explaining ways to contact health professionals regarding informational or emotional support would fill a gap that currently is met by other aspects of their network.


Experimentally infected domestic ducks show efficient transmission of Indonesian H5N1 highly pathogenic avian influenza virus, but lack persistent viral shedding.
Ducks are important maintenance hosts for avian influenza, including H5N1 highly pathogenic avian influenza viruses. A previous study indicated that persistence of H5N1 viruses in ducks after the development of humoral immunity may drive viral evolution following immune selection. As H5N1 HPAI is endemic in Indonesia, this mechanism may be important in understanding H5N1 evolution in that region. To determine the capability of domestic ducks to maintain prolonged shedding of Indonesian clade 2.1 H5N1 virus, two groups of Pekin ducks were inoculated through the eyes, nostrils and oropharynx and viral shedding and transmission investigated. Inoculated ducks (n = 15), which were mostly asymptomatic, shed infectious virus from the oral route from 1 to 8 days post inoculation, and from the cloacal route from 2-8 dpi. Viral ribonucleic acid was detected from 1-15 days post inoculation from the oral route and 1-24 days post inoculation from the cloacal route (cycle threshold <40). Most ducks seroconverted in a range of serological tests by 15 days post inoculation. Virus was efficiently transmitted during acute infection (5 inoculation-infected to all 5 contact ducks). However, no evidence for transmission, as determined by seroconversion and viral shedding, was found between an inoculation-infected group (n = 10) and contact ducks (n = 9) when the two groups only had contact after 10 days post inoculation. Clinical disease was more frequent and more severe in contact-infected (2 of 5) than inoculation-infected ducks (1 of 15). We conclude that Indonesian clade 2.1 H5N1 highly pathogenic avian influenza virus does not persist in individual ducks after acute infection.


Speaker-individuality in suprasegmental temporal features: Implications for forensic voice comparison.
Everyday experience tells us that it is often possible to identify a familiar speaker solely by his/her voice. Such observations reveal that speakers carry individual features in their voices. The present study examines how suprasegmental temporal features contribute to speaker-individuality. Based on data of a homogeneous group of Zurich German speakers, we conducted an experiment that included speaking style variability (spontaneous vs. read speech) and channel variability (high-quality vs. mobile phone-transmitted speech), both of which are characteristic of forensic casework. Speakers demonstrated high between-speaker variability in both read and spontaneous speech, and low within-speaker variability across the two speaking styles. Results further revealed that distortions of the type introduced by mobile telephony had little effect on suprasegmental temporal characteristics. Given this evidence of speaker-individuality, we discuss suprasegmental temporal features' potential for forensic voice comparison.


Hypertension in High School Students: Genetic and Environmental Factors: The HYGEF Study.
Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1β (interleukin 1β) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.


Senescence of T Lymphocytes: Implications for Enhancing Human Immunity.
As humans live longer, a central concern is to find ways to maintain their health as they age. Immunity declines during ageing, as shown by the increased susceptibility to infection by both previously encountered and new pathogens and by the decreased efficacy of vaccination. It is therefore crucial to understand the mechanisms responsible for this decrease in immunity and to develop new strategies to enhance immune function in older humans. We discuss here how the induction of senescence alters leukocyte, and specifically T cell, function. An emerging concept is that senescence and nutrient sensing-signalling pathways within T cells converge to regulate functional responses, and the manipulation of these pathways may offer new ways to enhance immunity during ageing.


Construction of a bacterial artificial chromosome (BAC) contig across the minimally deleted region in 13q14.3 in B-cell chronic lymphocytic leukemia.
Loss of heterozygosity (LOH) analysis in B-cell chronic lymphocytic leukemia (BCLL) has indicated that a frequent genetic event is loss of alleles from an approximately 500 kb region in 13q14.3, distal to the retinoblastoma gene. We have used DNA markers from this region to isolate and characterize a series of bacterial artificial chromosomes (BACs) which span the region between markers D13S319 and D13S25, which represents the common region of LOH. This entire region appears to be contained within only two minimally overlapping BACs, representing a maximum distance of approximately 350 kb. This BAC contig has been used to position known STS, EST and gene markers within the region. We have also used a modified differential display/RNA fingerprinting procedure designed to isolated transcribed sequences from YACs to isolate two transcribed units from the region which have also been positioned within the contig. The construction of a BAC contig with minimal redundancy provides the ideal resources from which to begin to identify candidate genes related to BCLL.


A Self-nanoemulsifying Drug Delivery System for Poorly Water Soluble Tolbutamide: Development, Optimization and Pharmacodynamic Studies.
Self-nanoemulsifying drug delivery system (SNEDDS) has immense potential in oral bioavailability enhancement of lipophilic drugs. This investigation involves the development of thermodynamically stable and dilutable SNEDDS for tolbutamide, for achieving higher water solubility and enhanced dissolution rate which in turn improves its oral bioavailability. Preliminary solubility studies were carried out and pseudo-ternary phase diagrams were plotted for selection of best ratio of surfactant and co-surfactant. The drug loaded SNEDDS were prepared, characterized w.r.t. refractive index, viscocity, globule size, zeta potential, and TEM, and converted into solid self-nanoemulsifying granules (SSNEGs). These were further characterized and their antidiabetic efficacy in male Wistar rats was evaluated. Solubility studies suggested the suitability of oleic acid as lipid phase; Tween 20 and PEG 400 as optimal surfactant and co-surfactant, respectively for formulation of SNEDDS formulations. The optimal SNEDDS formulation having mean globule diameter, viscosity, polydispersity 58.55 ± 0.2 nm, 26.18 ± 0.2 cps, 0.277 respectively, and infinite dilution capability displayed a highly significant increase in dissolution rate within 5 h compared to pure drug suspension. The SSNEGs showed 1.54 fold increase in drug dissolution rate compared to pure drug. Stability studies revealed no significant change in morphology and globule size. Anti-hyperglycemic activity of tolbutamide loaded SSNEGs in rats showed a significant reduction in elevated blood glucose level with absence of ketone and glucose in urine. The present study demonstrates a successful development of SNEDDS formulation with an overall potential of bioavailability enhancement for tolbutamide, a BCS-II drug.


The Benefit of Moderate Alcohol Use on Mood and Functional Ability in Later Life: Due to Beers or Frequent Cheers?
Evidence relates moderate alcohol consumption in later life to fewer depressive symptoms and greater functional ability. This study evaluated social interaction as a mediator of these outcomes. Data included older adults in the Health and Retirement Study. In Study 1, cross-sectional mediation analyses evaluated social interaction as a mechanism through which moderate alcohol use was related to decreased depressive symptomatology (Model 1; N = 2,294) and less functional limitation (Model 2; N = 2,357). In Study 2, longitudinal cross-lagged path analyses further evaluated the impact of moderate alcohol use and social interaction on future depressive symptoms and functional limitation. In Study 1, results from Model 1 indicated that moderate alcohol use was associated with decreased depressive symptomatology indirectly via greater social interaction. In Model 2, moderate alcohol use was associated with less functional limitation indirectly via greater social interaction. In Study 2, significant indirect effects corroborated findings from Study 1. In Model 3, moderate alcohol use in 2012 inversely predicted depressive symptomatology in 2014 via greater levels of social interaction in 2012. In Model 4, moderate alcohol use in 2012 predicted less functional limitation in 2014 via greater social interaction in 2012. Social interaction is essential to the seemingly beneficial effect of moderate alcohol use on depressive symptomatology and functional ability. Clinically, this suggests caution in attributing health benefits to consumption of alcohol itself and identifies social interaction as a treatment target for improved health outcomes in later life.


Plantar Sole Unweighting Alters the Sensory Transmission to the Cortical Areas.
It is well established that somatosensory inputs to the cortex undergo an early and a later stage of processing. The later has been shown to be enhanced when the earlier transmission decreased. In this framework, mechanical factors such as the mechanical stress to which sensors are subjected when wearing a loaded vest are associated with a decrease in sensory transmission. This decrease is in turn associated with an increase in the late sensory processes originating from cortical areas. We hypothesized that unweighting the plantar sole should lead to a facilitation of the sensory transmission. To test this hypothesis, we recorded cortical somatosensory evoked potentials (SEPs) of individuals following cutaneous stimulation (by mean of an electrical stimulation of the foot sole) in different conditions of unweighting when standing still with eyes closed. To this end, the effective bodyweight (BW) was reduced from 100% BW to 40% BW. Contrary to what was expected, we found an attenuation of sensory information when the BW was unweighted to 41% which was not compensated by an increase of the late SEP component. Overall these results suggested that the attenuation of sensory transmission observed in 40 BW condition was not solely due to the absence of forces acting on the sole of the feet but rather to the current relevance of the afferent signals related to the balance constraints of the task.


The risk of lung cancer with increasing time since ceasing exposure to asbestos and quitting smoking.
To examine if the risk of lung cancer declines with increasing time since ceasing exposure to asbestos and quitting smoking, and to determine the relative asbestos effect between non-smokers and current smokers. A cohort study of 2935 former workers of the crocidolite mine and mill at Wittenoom, who responded to a questionnaire on smoking first issued in 1979 and on whom quantitative estimates of asbestos exposure are known. Conditional logistic regression was used to relate asbestos exposure, smoking category, and risk of lung cancer. Eighteen per cent of the cohort reported never smoking; 66% of cases and 50% of non-cases were current smokers. Past smokers who ceased smoking within six years of the survey (OR = 22.1, 95% CI 5.6 to 87.0), those who ceased smoking 20 or more years before the survey (OR = 1.9, 95% CI 0.50 to 7.2), and current smokers (<20 cigarettes per day (OR = 6.8, 95% CI 2.0 to 22.7) or >20 cigarettes per day (OR = 13.2, 95% CI 4.1 to 42.5)) had higher risks of lung cancer compared to never smokers after adjusting for asbestos exposure and age. The asbestos effect between non-smokers and current smokers was 1.23 (95% CI 0.35 to 4.32). Persons exposed to asbestos and tobacco but who subsequently quit, remain at an increased risk for lung cancer up to 20 years after smoking cessation, compared to never smokers. Although the relative risk of lung cancer appears higher in never and ex-smokers than in current smokers, those who both smoke and have been exposed to asbestos have the highest risk; this study emphasises the importance of smoking prevention and smoking cessation programmes within this high risk cohort.


European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.
Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.


Biological, molecular, and structural analysis of a cytopathic variant from a molecularly cloned simian immunodeficiency virus.
Some isolates of simian immunodeficiency virus (SIV) have been shown to infect Sup-T1 cells with slow kinetics and in the absence of cytopathic effects, including cell fusion or CD4 down-modulation (J. A. Hoxie, B. S. Haggarty, S. Bonser, J. Rackowski, H. Shan, and P. Kanki, J. Virol. 62:2557-2568, 1988). In the present study, we describe the isolation and characterization of a SIVmac variant, derived from the BK28 infectious molecular clone, that became highly cytopathic for Sup-T1 cells. This variant, termed CP-MAC, exhibited a number of differences from BK28, including (i) an altered tropism which largely restricted its host range to Sup-T1 cells, (ii) the ability to induce cell fusion and CD4 down-modulation, and (iii) a highly stable interaction of its external (SU) and transmembrane (TM) envelope glycoproteins. In addition, a marked increase in the level of surface envelope glycoproteins was observed both on CP-MAC-infected cells and on virions. The CP-MAC env gene was PCR amplified from infected cells, and sequence analysis identified five amino acid changes in SU and six in TM compared with BK28. The introduction of these changes into BK28 was shown to fully reconstitute the biological and morphological properties of CP-MAC. The limited number of mutations in CP-MAC should enable the molecular determinants to be more precisely defined and help to identify the underlying mechanisms responsible for the striking biological and structural alterations exhibited by this virus.


Clozapine-induced serositis: review of its clinical features, pathophysiology and management strategies.
Although the benefits of clozapine have been well demonstrated in resistant schizophrenia, the frequency of adverse events is of particular concern: up to 76% of patients to whom clozapine was prescribed experienced an adverse event, with a discontinuation rate of 17%. In addition to its major clinical side effect, agranulocytosis, clozapine is reported to induce inflammatory syndromes with polyserositis. Apart from sparse case reports, no study has yet addressed this particularly interesting issue. With the aim of improving the outcome of clozapine-treated patients, we undertook a review of the literature to characterize the clinical features of clozapine-induced serositis, its pathophysiology, and to propose strategies of clinical management.


A common genetic system for functional studies of pitrilysin and related M16A proteases.
Pitrilysin is a bacterial protease that is similar to the mammalian insulin-degrading enzyme, which is hypothesized to protect against the onset of Alzheimer's disease, and the yeast enzymes Axl1p and Ste23p, which are responsible for production of the a-factor mating pheromone in Saccharomyces cerevisiae. The lack of a phenotype associated with pitrilysin deficiency has hindered studies of this enzyme. Herein, we report that pitrilysin can be heterologously expressed in yeast such that it functionally substitutes for the shared roles of Axl1p and Ste23p in pheromone production, resulting in a readily observable phenotype. We have exploited this phenotype to conduct structure-function analyses of pitrilysin and report that residues within four sequence motifs that are highly conserved among M16A enzymes are essential for its activity. These motifs include the extended metalloprotease motif, a second motif that has been hypothesized to be important for the function of M16A enzymes, and two others not previously recognized as being important for pitrilysin function. We have also established that the two self-folding domains of pitrilysin are both required for its proteolytic activity. However, pitrilysin does not possess all the enzymatic properties of the yeast enzymes since it cannot substitute for the role of Axl1p in the repression of haploid invasive growth. These observations further support the utility of the yeast system for structure-function and comparative studies of M16A enzymes.


Biochemical assessment of patients following ketogenic diets for epilepsy: Current practice in the UK and Ireland.
Biochemical assessment is recommended for patients prior to initiating and following a ketogenic diet (KD). There is no published literature regarding current practice in the UK and Ireland. We aimed to explore practice in comparison with international guidelines, determine approximate costs of biochemical testing in KD patients across the UK and Ireland, and promote greater consistency in KD services nationally. A survey was designed to determine the biochemical tests requested for patients at baseline, 3, 6, 12, 18, and 24 months + on KD. The survey was circulated to 39 centers across the UK and Ireland. Sixteen centers completed the survey. Full blood count, electrolytes, calcium, liver function tests (LFTs), lipid profile, and vitamin D were requested at all centers at baseline, in keeping with international guidelines. Bicarbonate, total protein, and urinalysis were less consistently requested. Magnesium and zinc were requested by all centers, despite not being specifically recommended for pre-diet evaluation in guidelines. Urea and electrolyte profiles and some LFTs were consistently requested at follow-up, in accordance with guidelines. Other LFTs and renal tests, full blood count, lipid profile, acylcarnitine profile, selenium, vitamin D, and urinalysis were less consistently requested at follow-up. The mean costs of the lowest and highest number of tests requested at baseline in our participating centers were £167.54 and £501.93; the mean costs of the lowest and highest number of tests requested at 3-month follow-up were £19.17 and £450.06. Biochemical monitoring of KD patients varies widely across the UK and Ireland and does not fully correspond to international best practice guidelines. With an ongoing drive for cost-effectiveness within health care, further work is needed to streamline practice while ensuring patient safety.


The inpatient fracture neck of femur: an important subgroup of patients.
Fractured neck of femur (FNOF) is an increasing problem for the National Health Service (NHS) with 61,508 recorded on the National Hip Fracture Database (NHFD) in 2012–2013 and treatment of such patients is estimated to cost the NHS £1.5 billion per year. Inpatients falling in hospital and sustain a FNOF have rarely been studied as a separate group of patients to assess standards of patient care, time to operative management, and patient mortality. Of 694 patients sustaining an acute FNOF at a single trust between January 2012 and June 2013, 40 patients (5.8%) sustained an inpatient FNOF. 19 patients (47.5%) were male and 15 patients (37.5%) had an ASA grade of 4 or 5, compared to 153 patients (23.4%) and 127 patients (19.4%) respectively of "community" FNOF. 39 of 40 patients received operative management. Patients with an "inpatient" FNOF were less likely to be admitted to an orthopaedic ward within 4 h (30%) and receive operative management within 48 h (65%) according to "Blue Book" standards. Results according to best practice tariff (BPT) were also significantly reduced for the "inpatient" FNOF group, with 23 patients (57.5%) receiving operative management within 36 h and only 19 patients (47.5%) achieving BPT compared to 76.5% and 72.5% respectively for "community" FNOF patients. Mortality among inpatients reached 40% at 120 days and 50% at 1 year, significantly higher than community FNOF patients after multivariate analysis. Patients sustaining an "inpatient" FNOF are more likely to have significant medical co-morbidity and require aggressive medical and surgical management, especially due to their increased risk of mortality post-operatively. Such injuries have direct and indirect financial implications to a health care trust, which can be minimised by prompt management of these patients. This study highlights the need for a standardised protocol of management of this important subgroup of patients and for further work on falls prevention strategies within the National Health Service.


Modeling Trajectories of Sensation Seeking and Impulsivity Dimensions from Early to Late Adolescence: Universal Trends or Distinct Sub-groups?
Developmental imbalance models attribute the rise in risk-taking during adolescence to a universal imbalance between rising reward sensitivity and lagging cognitive control. This study tested predictions of an alternate Lifespan Wisdom Model that distinguishes between exploratory/adaptive (e.g., sensation seeking) and maladaptive (e.g., acting-without-thinking, delay discounting) risk-taking propensities and attributes the latter to a sub-set of youth with weak cognitive control. Latent trajectory modeling of six waves of data from 387 adolescents (52% females; spanning average ages of 11-18 years) revealed distinct sub-groups with heterogeneous trajectory patterns for acting-without-thinking and delay-discounting. Only those trajectory groups with weak cognitive control, characterized as "high-increasing" acting-without thinking and "high-stable" delay discounting were predictive of a maladaptive risk-taking outcome, namely substance use disorder. Sensation seeking demonstrated a universal peak, but high levels of sensation seeking were not associated with weakness in cognitive control and were unrelated to substance use disorder, controlling for impulsivity. The findings suggest that maladaptive risk-taking characterized by weak cognitive control over reward-driven impulses is a phenomenon limited to only a sub-set of youth.


The amphibian epidermis: distribution of mitochondria-rich cells and the effect of oxytocin.
It is known that the ion-transporting capacity and the permeability to water of amphibian skins vary greatly both between and within species. Furthermore, the extent to which different skins respond to hormonal stimulation of these parameters also shows considerable inter- and intra-specific variation. As a first step towards defining a possible morphological basis for this physiological heterogeneity, we examined different regions of skins from 3 anurans, Bufo bufo, Rana ridibunda and Xenopus laevis, that are species with widely differing habitats. The mitochondria-rich cell population of the epidermis was counted and the epidermal thickness was measured. There were large differences in the mitochondria-rich cell content and in the epidermal thickness of the skins from different species and from different regions of skin from the same animal. In a second set of studies, the same morphological features were examined and, in addition, routine functional parameters were measured to monitor some transport properties of the skins used. The skins also varied considerably with respect to short-circuit current, potential difference, water permeability and sensitivity to oxytocin. Although no apparent relationship was noted between either basal or hormone-stimulated physiological parameters and the morphological features of the individual skins, the striking variation in the density of mitochondria-rich cells in amphibian epidermis merits further studies, including the use of techniques or experimental designs that allow the movement of individual species of ion across the skin to be followed.


Groundwater Governance in a Water-Starved Country: Public Policy, Farmers' Perceptions, and Drivers of Tubewell Adoption in Balochistan, Pakistan.
Pakistan faces the challenge of developing sustainable groundwater policies with the main focus on groundwater management rather than groundwater development and with appropriate governance arrangement to ensure benefits continue into the future. This article investigates groundwater policy, farmers' perceptions, and drivers of tubewell (groundwater bore) adoption and proposes possible pathways for improved groundwater management for Balochistan, Pakistan. Historical groundwater policies were mainly aimed at increasing agricultural production and reducing poverty, without consideration of adverse impact on groundwater availability. These groundwater policies and governance arrangements have resulted in a massive decline in groundwater tables. Tubewell owners' rankings of the drivers of groundwater decline suggest that rapid and widespread installation of tubewells, together with uncontrolled extraction due to lack of property rights, electricity subsidy policies, and ineffective governance, are key causes of groundwater decline in Balochistan. An empirical "tubewell adoption" model confirmed that the electricity subsidy significantly influenced tubewell adoption decisions. The article proposes a more rational electricity subsidy policy for sustaining groundwater levels in the short-run. However, in the long run a more comprehensive sustainable groundwater management policy, with strong institutional support and involvement of all stakeholders, is needed.


Behavior of the DPH fluorescence probe in membranes perturbed by drugs.
1,6-Diphenyl-1,3,5-hexatriene (DPH) is one of the most commonly used fluorescent probes to study dynamical and structural properties of lipid bilayers and cellular membranes via measuring steady-state or time-resolved fluorescence anisotropy. In this study, we present a limitation in the use of DPH to predict the order of lipid acyl chains when the lipid bilayer is doped with itraconazole (ITZ), an antifungal drug. Our steady-state fluorescence anisotropy measurements showed a significant decrease in fluorescence anisotropy of DPH embedded in the ITZ-containing membrane, suggesting a substantial increase in membrane fluidity, which indirectly indicates a decrease in the order of the hydrocarbon chains. This result or its interpretation is in disagreement with the fluorescence recovery after photobleaching measurements and molecular dynamics (MD) simulation data. The results of these experiments and calculations indicate an increase in the hydrocarbon chain order. The MD simulations of the bilayer containing both ITZ and DPH provide explanations for these observations. Apparently, in the presence of the drug, the DPH molecules are pushed deeper into the hydrophobic membrane core below the lipid double bonds, and the probe predominately adopts the orientation of the ITZ molecules that is parallel to the membrane surface, instead of orienting parallel to the lipid acyl chains. For this reason, DPH anisotropy provides information related to the less ordered central region of the membrane rather than reporting the properties of the upper segments of the lipid acyl chains.


Influence of Polymer Charge on the Localization and Dark- and Photo-Induced Toxicity of a Potential Type I Photosensitizer in Cancer Cell Models.
A current trend within photo-dynamic therapy (PDT) is the development of molecular systems targeting hypoxic tumors. Thus, type I PDT sensitizers could here overcome traditional type II molecular systems that rely on the photo-initiated production of toxic singlet oxygen. Here, we investigate the cell localization properties and toxicity of two polymeric anthracene-based fluorescent probes (neutral Ant-PHEA and cationic Ant-PIm). The cell death and DNA damage of Chinese hamster ovary cancer cells (CHO-K1) were characterized as combining PDT, cell survival studies (MTT-assay), and comet assay. Confocal microscopy was utilized on samples incubated together with either DRAQ5, Lyso Tracker Red, or Mito Tracker Deep Red in order to map the localization of the sensitizer into the nucleus and other cell compartments. While Ant-PHEA did not cause significant damage to the cell, Ant-PIm showed increased cell death upon illumination, at the cost of a significant dark toxicity. Both anthracene chromophores localized in cell compartments of the cytosol. Ant-PIm showed a markedly improved selectivity toward lysosomes and mitochondria, two important biological compartments for the cell's survival. None of the two anthracene chromophores showed singlet oxygen formation upon excitation in solvents such as deuterium oxide or methanol. Conclusively, the significant photo-induced cell death that could be observed with Ant-PIm suggests a possible type I PDT mechanism rather than the usual type II mechanism.


Cavity-mediated near-critical dissipative dynamics of a driven condensate.
We investigate the near-critical dynamics of atomic density fluctuations in the nonequilibrium self-organization transition of an optically driven quantum gas coupled to a single mode of a cavity. In this system cavity-mediated long-range interactions between atoms, tunable by the drive strength, lead to softening of an excitation mode recently observed in experiments. This phenomenon has previously been studied within a two-mode approximation for the collective motional degrees of freedom of the atomic condensate, which results in an effective open-system Dicke model. Here, including the full spectrum of atomic modes we find a finite lifetime for a rotonlike mode in the Bogoliubov excitation spectrum that is strongly pump dependent. The corresponding decay rate and critical exponents for the phase transition are calculated explaining the nonmonotonic pump-dependent atomic damping rate observed in recent experiments. We compute the near-critical behavior of the intracavity field fluctuations that has been previously shown to be enhanced with respect to the equilibrium Dicke model in a two-mode approximation. We highlight the role of the finite size of the system in the suppression of it below the expectations of the open Dicke model.


Identification of core subunits of photosystem II as action sites of HSP21, which is activated by the GUN5-mediated retrograde pathway in Arabidopsis.
Photosystem II (PSII) is the most thermolabile photosynthetic complex. Physiological evidence suggests that the small chloroplast heat-shock protein 21 (HSP21) is involved in plant thermotolerance, but the molecular mechanism of its action remains largely unknown. Here, we have provided genetic and biochemical evidence that HSP21 is activated by the GUN5-dependent retrograde signaling pathway, and stabilizes PSII by directly binding to its core subunits such as D1 and D2 proteins under heat stress. We further demonstrate that the constitutive expression of HSP21 sufficiently rescues the thermosensitive stability of PSII and survival defects of the gun5 mutant with dramatically improving granal stacking under heat stress, indicating that HSP21 is a key chaperone protein in maintaining the integrity of the thylakoid membrane system under heat stress. In line with our interpretation based on several lines of in vitro and in vivo protein-interaction evidence that HSP21 interacts with core subunits of PSII, the kinetics of HSP21 binding to the D1 and D2 proteins was determined by performing an analysis of microscale thermophoresis. Considering the major role of HSP21 in protecting the core subunits of PSII from thermal damage, its heat-responsive activation via the heat-shock transcription factor HsfA2 is critical for the survival of plants under heat stress. Our findings reveal an auto-adaptation loop pathway that plant cells optimize particular needs of chloroplasts in stabilizing photosynthetic complexes by relaying the GUN5-dependent plastid signal(s) to activate the heat-responsive expression of HSP21 in the nucleus during adaptation to heat stress in plants.


Contribution of semi-arid forests to the climate system.
Forests both take up CO2 and enhance absorption of solar radiation, with contrasting effects on global temperature. Based on a 9-year study in the forests' dry timberline, we show that substantial carbon sequestration (cooling effect) is maintained in the large dry transition zone (precipitation from 200 to 600 millimeters) by shifts in peak photosynthetic activities from summer to early spring, and this is counteracted by longwave radiation (L) suppression (warming effect), doubling the forestation shortwave (S) albedo effect. Several decades of carbon accumulation are required to balance the twofold S + L effect. Desertification over the past several decades, however, contributed negative forcing at Earth's surface equivalent to approximately 20% of the global anthropogenic CO2 effect over the same period, moderating warming trends.


The clinical relevance of a repeat biopsy in lupus nephritis flares.
The clinical utility of performing repeat biopsies during lupus nephritis flares is questionable and data pointing towards frequent class switches are based on the old WHO classification. This retrospective study investigates the hypothesis that clinically relevant switches from proliferative to non-proliferative lesions and vice versa as determined by the new ISN/RPS classification are a rare event and that repeat biopsies are unnecessary in many cases. Thirty-five patients with lupus nephritis and one or more repeat renal biopsies were included. Eighty-four biopsies were blindly reassessed according to the ISN/RPS classification. Twenty-five patients had one repeat biopsy, 6 patients had two and 4 patients had three repeat biopsies. Forty-nine comparisons between reference and repeat biopsies could be made. In 25 cases (54.3%), there was no shift in ISN/RPS class on repeat biopsies. In 41 instances, paired biopsies showed proliferative lesions both on reference and repeat biopsies, whereas five of six cases with non-proliferative lesions on a reference biopsy switched to proliferative lesions on a repeat biopsy. Clinically significant class switches during lupus nephritis flares were more frequent in patients with non-proliferative lesions in their reference biopsy (P < 0.001). The results show that patients with proliferative lesions in the original biopsy rarely switch to a pure non-proliferative nephritis during a flare. Therefore, a repeat biopsy during a lupus nephritis flare is frequently not necessary if proliferative lesions were found in the reference biopsy. However, in the case of a non-proliferative lesion in the reference biopsy, class switches are frequently found and repeat biopsies are advisable.


An international survey of pelvic trauma surgeons on the management of pelvic ring injuries.
There exists substantial variability in the management of pelvic ring injuries among pelvic trauma surgeons. The objective of this study was to perform a comprehensive survey on the management of pelvic ring injuries among an international group of pelvic trauma surgeons to determine areas of agreement and disagreement. A 45-item questionnaire was developed using an online survey platform and distributed to 30 international pelvic trauma surgeons. The survey consisted of general questions on the acute management of pelvic ring injuries and questions regarding 5 cases: Lateral compression (LC) type 1 injury, LC-3, Anterior-posterior compression (APC) type 3 injury, a combined vertical shear (VS) injury through the sacrum, and VS injury through sacroiliac joint. Respondents were shown blinded anteroposterior pelvis radiographs and axial computed tomography (CT) images for each case and asked if the injury needed fixation, the type of fixation, the order of fixation, and postoperative weight-bearing status. The Kappa statistic was calculated to assess agreement between respondents for each question. Nineteen out of 30 pelvic trauma surgeons completed the survey. Respondents practiced in Brazil (n = 1), Germany (n = 1), India (n = 1), Italy (n = 1) United Kingdom (n = 1), and the United States (n = 14). Of the 45 questions in this survey, 38 (84%) had minimal to no agreement among the respondents. There was moderate agreement, for performing lumbopelvic fixation when indicated, for anterior and posterior fixation of the LC-3 injury, and on forgoing EUA or stress X-rays for the APC-3 injury. There was strong agreement for open reduction and internal fixation of the anterior pelvic ring in the APC-3 injury and the VS injury through the SI joint. In contrast, LC-1 injury and combined VS pelvic ring injury through the sacrum had no areas of moderate to strong agreement. This study identified specific areas of pelvic ring injury management with minimal to no agreement among pelvic trauma surgeons. Future research should target these areas with a lack of agreement to decrease practice variability and improve patient outcomes.


A regulatory role for 1-acylglycerol-3-phosphate-O-acyltransferase 2 in adipocyte differentiation.
Mutations in the 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) gene have been identified in individuals affected with congenital generalized lipodystrophy (CGL). AGPAT2 catalyzes acylation of lysophosphatidic acid to phosphatidic acid, a precursor for both triacylglycerol (TAG) and phospholipid synthesis. Recent studies suggest that reduced AGPAT2 enzymatic activity may underlie the CGL clinical phenotype. To gain insight into how altered AGPAT2 activity causes lipodystrophy, we examined the effect of knockdown of AGPAT2 expression in preadipocytes on TAG synthesis and storage, and on adipocyte differentiation. We show that AGPAT2 mRNA expression is induced 30-fold during adipocyte differentiation and that AGPAT2 enzymatic activity is required for TAG mass accumulation in mature adipocytes. We demonstrate that small interference RNA-mediated knockdown of AGPAT2 expression prevents appropriate early induction of C/EBPbeta and PPARgamma, key transcriptional activators of the adipogenic program, and delays expression of multiple adipocyte-related genes. The unexpected finding, that levels of several phospholipid species, including phosphatidic acid (PA), are elevated in TAG-depleted adipocytes with AGPAT2 knockdown, suggests that impaired AGPAT2 activity affects availability of PA for TAG synthesis but not overall PA synthesis nor utilization of PA for phospholipid synthesis. These findings underscore the importance of an AGPAT2-mediated metabolic pathway in adipocyte differentiation.


n-3 Polyunsaturated Fatty Acid Amides: New Avenues in the Prevention and Treatment of Breast Cancer.
Over the last decades a renewed interest in n-3 very long polyunsaturated fatty acids (PUFAs), derived mainly from fish oils in the human diet, has been observed because of their potential effects against cancer diseases, including breast carcinoma. These n-3 PUFAs mainly consist of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that, alone or in combination with anticancer agents, induce cell cycle arrest, autophagy, apoptosis, and tumor growth inhibition. A large number of molecular targets of n-3 PUFAs have been identified and multiple mechanisms appear to underlie their antineoplastic activities. Evidence exists that EPA and DHA also elicit anticancer effects by the conversion to their corresponding ethanolamide derivatives in cancer cells, by binding and activation of different receptors and distinct signaling pathways. Other conjugates with serotonin or dopamine have been found to exert anti-inflammatory activities in breast tumor microenvironment, indicating the importance of these compounds as modulators of tumor epithelial/stroma interplay. The objective of this review is to provide a general overview and an update of the current n-3 PUFA derivative research and to highlight intriguing aspects of the potential therapeutic benefits of these low-toxicity compounds in breast cancer treatment and care.


A novel in situ probe for oxygen uptake rate measurement in mammalian cell cultures.
The newly developed in situ oxygen uptake rate (in situ OUR) probe presented in this article is based on the in situ microscope technology platform. It is designed to measure the oxygen uptake rate (OUR) of mammalian cells, an important parameter for metabolic flux analysis, inside a reactor (in situ) and in real-time. The system isolates a known volume of cell culture from the bulk inside the bioreactor, monitors the oxygen consumption over time, and releases the sample again. The sample is mixed during the measurement with a new agitation system to keep the cells in suspension and prevent oxygen concentration gradients. The OUR measurement system also doubles as a standard dissolved oxygen (DO) probe for process monitoring when it is not performing OUR measurements. It can be equipped with two different types of optical sensors (i.e., DO, pH) simultaneously or a conventional polarographic DO-probe (Clark type). This new probe was successfully tested in baby hamster kidney perfusion cell cultures.


The impact of surgery in metastatic pancreatic neuroendocrine tumors: a competing risk analysis.
Aim The role of surgery in the treatment of metastatic pancreatic neuroendocrine tumors (PNETs) was controversial. The objectives of this study were to illustrate the impact of surgery in improving the prognosis of patients with metastatic PNETs and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) based on a large population-based cohort. Methods Patients diagnosed with metastatic PNETs between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Nomograms for estimating OS and CSS were established based on Cox regression model and Fine and Grey's model. The precision of the nomograms was evaluated and compared using concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC). Results The study cohort included 1966 patients with metastatic PNETs. It was shown that the surgery provided survival benefit for all groups of patients with metastatic PNETs. In the whole study cohort, 1-, 2- and 3-year OS and CSS were 51.5, 37.1 and 29.4% and 53.0, 38.9 and 31.1%, respectively. The established nomograms were well calibrated, and had good discriminative ability, with C-indexes of 0.773 for OS prediction and 0.774 for CSS prediction. Conclusions Patients with metastatic PNETs could benefit from surgery when the surgery tolerance was acceptable. The established nomograms could stratify patients who were categorized as tumor-node-metastasis (TNM) IV stage into groups with diverse prognoses, showing better discrimination and calibration of the established nomograms, compared with 8th TNM stage system in predicting OS and CSS for patients with metastatic PNETs.


In situ bypass and extra-anatomic bypass procedures result in similar survival in patients with secondary aortoenteric fistulas.
The optimal revascularization modality in secondary aortoenteric fistula (SAEF) remains unclear in the literature. The purpose of this investigation was to determine the revascularization approach associated with the lowest morbidity and mortality using real-world data in patients with SAEF. A retrospective, multi-institutional study of SAEF from 2002 to 2014 was performed using a standardized database. Baseline demographics, comorbidities, and operative and postoperative variables were recorded. The primary outcome was long-term mortality. Descriptive statistics, Kaplan-Meier survival analysis, and univariate and multivariate analyses were performed. During the study period, 182 patients at 34 institutions from 11 countries presented with SAEF (median age, 72 years; 79% male). The initial aortic procedures that resulted in SAEF were 138 surgical grafts (76%) and 42 endografts (23%), with 2 unknown; 102 of the SAEFs (56%) underwent complete excision of infected aortic graft material, followed by in situ (in-line) bypass (ISB), including antibiotic-soaked prosthetic graft (53), autogenous femoral vein (neoaortoiliac surgery; 17), cryopreserved allograft (28), and untreated prosthetic grafts (4). There were 80 patients (44%) who underwent extra-anatomic bypass (EAB) with infected graft excision. Overall median Kaplan-Meier estimated survival was 319 days (interquartile range, 20-2410 days). Stratified by EAB vs ISB, there was no significant difference in Kaplan-Meier estimated survival (P = .82). In comparing EAB vs ISB, EAB patients were older (74 vs 70 years; P = .01), had less operative hemorrhage (1200 mL vs 2000 mL; P = .04), were more likely to initiate dialysis within 30 days postoperatively (15% vs 5%; P = .02), and were less likely to experience aorta-related hemorrhage within 30 days postoperatively (3% aortic stump dehiscence vs 11% anastomotic rupture; P = .03). There were otherwise no significant differences in presentation, comorbidities, and intraoperative or postoperative variables. Multivariable Cox regression showed that the duration of antibiotic use (hazard ratio, 0.92; 95% confidence interval, 0.86-0.98; P = .01) and rifampin use at time of discharge (hazard ratio, 0.20; 95% confidence interval, 0.05-0.86; P = .03) independently decreased mortality. These data suggest that ISB does not offer a survival advantage compared with EAB and does not decrease the risk of postoperative aorta-related hemorrhage. After repair, <50% of SAEF patients survive 10 months. Each week of antibiotic use decreases mortality by 8%. Further study with risk modeling is imperative for this population.


A Drosophila model for primary coenzyme Q deficiency and dietary rescue in the developing nervous system.
Coenzyme Q (CoQ) or ubiquinone is a lipid component of the electron transport chain required for ATP generation in mitochondria. Mutations in CoQ biosynthetic genes are associated with rare but severe infantile multisystemic diseases. CoQ itself is a popular over-the-counter dietary supplement that some clinical and rodent studies suggest might be beneficial for neurodegenerative diseases. Here, we identify mutations in the Drosophila qless gene, which encodes an orthologue of the human PDSS1 prenyl transferase that synthesizes the isoprenoid side chain of CoQ. We show that neurons lacking qless activity upregulate markers of mitochondrial stress and undergo caspase-dependent apoptosis. Surprisingly, even though experimental inhibition of caspase activity did not prevent mitochondrial disruption, it was sufficient to rescue the size of neural progenitor clones. This demonstrates that, within the developing larval CNS, qless activity is required primarily for cell survival rather than for cell growth and proliferation. Full rescue of the qless neural phenotype was achieved by dietary supplementation with CoQ4, CoQ9 or CoQ10, indicating that a side chain as short as four isoprenoid units can provide in vivo activity. Together, these findings show that Drosophila qless provides a useful model for studying the neural effects of CoQ deficiency and dietary supplementation.


Macrophage Inflammatory Protein-1 Beta and Interferon Gamma Responses in Ugandans with HIV-1 Acute/Early Infections.
Control of HIV replication through CD4(+) and CD8(+) T cells might be possible, but the functional and phenotypic characteristics of such cells are not defined. Among cytokines produced by T cells, CCR5 ligands, including macrophage inflammatory protein-1 beta (MIP-1β), compete for the CCR5 coreceptor with HIV, promoting CCR5 internalization and decreasing its availability for virus binding. Interferon (IFN)-γ also has some antiviral activity and has been used as a read-out for T cell immunogenicity. We used cultured ELISpot assays to compare the relative contribution of MIP-1β and IFN-γ to HIV-specific responses. The magnitude of responses was 1.36 times higher for MIP-1β compared to IFN-γ. The breadth of the MIP-1β response (45.41%) was significantly higher than IFN-γ (36.88%), with considerable overlap between the peptide pools that stimulated both MIP-1β and IFN-γ production. Subtype A and D cross-reactive responses were observed both at stimulation and test level, but MIP-1β and IFN-γ responses displayed different effect patterns. We conclude that the MIP-1β ELISpot would be a useful complement to the evaluation of the immunogenicity of HIV vaccines and the activity of adjuvants.


Hypoxia and metabolism in cancer.
Interest in targeting metabolism has been renewed in recent years as research increases understanding of the altered metabolic profile of tumor cells compared with that of normal cells. Metabolic reprogramming allows cancer cells to survive and proliferate in the hostile tumor microenvironment. These metabolic changes support energy generation, anabolic processes, and the maintenance of redox potential, mechanisms that are all essential for the proliferation and survival of tumor cells. The metabolic switch in a number of key metabolic pathways is mainly regulated by genetic events, rendering cancer cells addicted to certain nutrients, such as glutamine. In addition, hypoxia is induced when highly proliferative tumor cells distance themselves from an oxygen supply. Hypoxia-inducible factor 1α is largely responsible for alterations in metabolism that support the survival of hypoxic tumor cells. Metabolic alterations and dependencies of cancer cells may be exploited to improve anticancer therapy. This chapter reviews the main aspects of altered metabolism in cancer cells, emphasizing recent advances in glucose, glutamine, and lipid metabolism.


Does time since fire drive live aboveground biomass and stand structure in low fire activity boreal forests? Impacts on their management.
Boreal forests subject to low fire activity are complex ecosystems in terms of structure and dynamics. They have a high ecological value as they contain important proportions of old forests that play a crucial role in preserving biodiversity and ecological functions. They also sequester important amounts of carbon at the landscape level. However, the role of time since fire in controlling the different processes and attributes of those forests is still poorly understood. The Romaine River area experiences a fire regime characterized by very rare but large fires and has recently been opened to economic development for energy and timber production. In this study, we aimed to characterize this region in terms of live aboveground biomass, merchantable volume, stand structure and composition, and to establish relations between these attributes and the time since the last fire. Mean live aboveground biomass and merchantable volume showed values similar to those of commercial boreal coniferous forests. They were both found to increase up to around 150 years after a fire before declining. However, no significant relation was found between time since fire and stand structure and composition. Instead, they seemed to mostly depend on stand productivity and non-fire disturbances. At the landscape level, this region contains large amounts of biomass and carbon stored resulting from the long fire cycles it experiences. Although in terms of merchantable volume these forests seemed profitable for the forest industry, a large proportion were old forests or presented structures of old forests. Therefore, if forest management was to be undertaken in this region, particular attention should be given to these old forests in order to protect biodiversity and ecological functions. Partial cutting with variable levels of retention would be an appropriate management strategy as it reproduces the structural complexity of old forests.


Type E2 glenoid bone loss orientation and management with augmented implants.
The purpose of this study was 2-fold: (1) to quantify type E2 bone loss orientation and its association with rotator cuff fatty infiltration and (2) to examine reverse baseplate designs used to manage type E2 glenoids. Computed tomography scans of 40 patients with type E2 glenoids were examined for pathoanatomic features and erosion orientation. The rotator cuff fatty infiltration grade was compared with the erosion orientation angle. To compare reconstructive options in light of the pathoanatomic findings, virtual implantation of 4 glenoid baseplate designs (standard, half wedge, full wedge, and patient-matched) was conducted to determine the volume of bone removal for seating and impingement-free range of motion. The mean type E2 erosion orientation angle was 47° ± 17° from the 0° superoinferior glenoid axis, resulting in the average erosion being located in the posterosuperior quadrant directed toward the 10:30 clock-face position. The type E2 neoglenoid, on average, involved 67% of the total glenoid surface (total surface area, 946 ± 209 mm2; neoglenoid surface area, 636 ± 247 mm2). The patient-matched baseplate design resulted in significantly (P ≤ .01) less bone removal (200 ± 297 mm3) for implantation, followed by the full-wedge design (1228 ± 753 mm3), half-wedge design (1763 ± 969 mm3), and standard (non-augmented) design (4009 ± 1210 mm3). We noted a marked difference in erosion orientation toward a more superior direction as the subscapularis fatty infiltration grade increased from grade 3 to grade 4 (P < .001). The average type E2 erosion orientation was directed toward the 10:30 clock-face position in the posterosuperior glenoid quadrant. This orientation resulted in the patient-matched glenoid augmentation requiring the least amount of bone removal for seating, followed by the full-wedge, half-wedge, and standard designs. Implant selection also substantially affected computationally derived range of motion in external rotation, flexion, extension, and adduction.


Evaluate the Usability of the Mobile Instant Messaging Software in the Elderly.
Instant messaging (IM) is one kind of online chat that provides real-time text transmission over the Internet. It becomes one of the popular communication tools. Even it is currnetly an era of smartphones, it still a great challenge to teach and promote the elderly to use smart phone. Besides, the acceptance of the elderly to use IM remains unknown. This study describes the usability and evaluates the acceptance of the IM in the elderly, who use the smartphone for the first time. This study is a quasi-experimental design study. The study period started from October, 2012 to December, 2013. There were totally 41 elderly recruited in the study. All of them were the first time to use LINE app on the smartphones. The usability was evaluated by using the Technology Acceptance Model which consisted of four constructs: cognitive usability, cognitive ease of use, attitude and willingness to use. Overall, the elderly had the best "attitude" for LINE APP communication software, with the highest rating averaging 4.07 points on four constructs, followed by an average of 4 points on "cognitive usefulness". The socres of "cognitive ease of use" and "willingness to use" scores were equal which are an average score of 3.86. It can be interpreted that (1) the elders thought that the LINE APP as an excellent communication tool for them; (2) they found the software is useful (3) it was convenient for them to communicate. However, it was necessary to additionally assist and explain the certain functions such as the options. It would play a great role in the "willingness to use". The positive acceptance of LINE APP in elderly refer to the probable similar acceptance for them to use other communication software. Encouraging the willingness the elderly to explore more technology products and understanding their behavior will be the basic knowledge to develop further software.


The design and development of drugs acting against the smallpox virus.
The eradication of smallpox was announced by the WHO in 1980. However, smallpox has not totally disappeared from people's minds because of its potential use as a biological weapon. Further outbreaks of smallpox would, needless to say, be devastating in a population, which has little or no immune defence against the virus. The real concerns come from the fact that the previously used vaccine would not be tolerated today by a number of patients and, more worryingly, there are no approved antiviral drugs against smallpox. This review is focused on the antiviral research, which has been stimulated to deliver potent inhibitors of the replication of the causative agent of smallpox, variola virus.